Alosetron

Alosetron

Systematic (IUPAC) name
5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one
Clinical data
Trade names	Lotronex
AHFS/Drugs.com	monograph
MedlinePlus	a601230
Pregnancy cat.	B (U.S.)
Legal status	℞-only (U.S.)
Routes	Oral
Pharmacokinetic data
Bioavailability	50–60%
Protein binding	82%
Metabolism	Hepatic (including CYP2C9, CYP3A4 and CYP1A2)
Half-life	1.5–1.7 hours
Excretion	Renal 73%, faecal 24%
Identifiers
CAS number	122852-42-0 Y
ATC code	A03AE01
PubChem	CID 2099
DrugBank	APRD00580
ChemSpider	2015 Y
UNII	13Z9HTH115 Y
KEGG	D07129 Y
ChEBI	CHEBI:253342 Y
ChEMBL	CHEMBL1110 Y
Chemical data
Formula	C17H18N4O
Mol. mass	294.351 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19) Y Key:JSWZEAMFRNKZNL-UHFFFAOYSA-N Y
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Alosetron (initial brand name: Lotronex; originator: GSK) is a 5-HT₃ antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex.

History

Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted; it was the first drug ever returned to the U.S. market after withdrawal for safety concerns.

In 2001, the editor of the renowned medical journal The Lancet, Richard Horton, critizised the FDA's handling of alosetron in an unusually sharp language. Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA's Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives of GlaxoSmithKline.

It is not known whether alosetron has been filed for registration in the EU.

GSK sold Lotronex to the Californian corporation Prometheus in late 2007.

Adverse effects

Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects. The cumulative incidence of ischaemic colitis was 2 in 1000, while serious complications arising from constipation (obstruction, perforation, impaction, toxic megacolon, secondary colonic ischaemia, death) was 1 in 1000.

Pharmacodynamics and mechanism of action

Alosetron has an antagonist action on the 5-HT₃ receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT₃ antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT₃ receptors is positively correlated with gastrointestinal motility, alosetron's 5-HT₃ antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.